Atypical Onset of Tics and Obsessive-Compulsive Symptoms in FXTAS Following COVID-19: A Case Report

Individuals carrying premutation (PM) alleles (55–200 CGG repeats) of the fragile X messenger ribonucleoprotein 1 (FMR1) gene typically exhibit normal cognitive abilities in early and midlife, unlike the childhood onset intellectual disability associated with fragile X syndrome (FXS). However, psychiatric disorders, such as anxiety, depression, and neurocognitive disorders, are common in these individuals from mid-life onward, affecting approximately 50% of premutation carriers [1]. These psychiatric co-morbidities are collectively referred to as fragile X-associated neuropsychiatric disorders (FXAND). While anxiety disorders are the most prevalent psychiatric co-morbidities among PM carriers, other associated conditions include depressive disorders, insomnia, obsessivecompulsive disorder (OCD), chronic pain, chronic fatigue syndrome, and late onset neurocognitive disorders [1,2]. As PM carriers age, between 40 to 75% of males and 16% of females [2,3], may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. FXTAS is characterized by gait ataxia, intention tremors, neuropathy, cognitive decline, and co-morbid psychiatric complications.

The diagnosis of FXTAS requires MRI imaging to identify white matter changes, including the middle cerebellar peduncle (MCP) sign, which is present in approximately 60% of males and 10% of females with FXTAS and is highly specific for FXTAS [4- 6]. In contrast, females are more likely to show white matter abnormalities in the splenium of the corpus callosum, Schneider et al reported a probability greater than 60% for women with FXTAS to present with high‐signal intensity in the splenium [6], though both genders may have the splenium sign and periventricular white matter disease [2,7,8]. Patients with the premutation may begin to exhibit symptoms of FXTAS in their 50s to 60s, with its prevalence increasing significantly with age. Around 38% of males in their 60s are affected, rising to as much as 75% by their 80s. Symptoms usually begin insidiously, with tremor as the initial sign, followed by balance difficulties and peripheral neuropathy in the lower extremities. Major neurocognitive disorder/dementia develops in approximately 50% of males with FXTAS but is less common in females, who also tend to experience a slower progression of the disease [8,9].

Motor and vocal tics, along with other involuntary movements, are not part of the recognized FXTAS phenotype. It is rare for tic disorders to emerge after the second decade of life. Typically, they first manifest during childhood, and in most cases, their severity decreases during adolescence, often reaching mild or minimal levels by early adulthood [10]. However, for some patients, tics do not follow this typical pattern and can persist, sometimes remaining severe well into adulthood [11]. Additionally, there are reports of Tourette syndrome (TS)-like symptoms emerging later in life, often because of neurological conditions such as stroke, encephalitis, or after exposure to certain medications [12-14]. Several characteristics are associated with tics. One of them is the feeling of an urge to perform the movement (premonition urge) with a transient sense of relief after the tic is performed. Tics are often voluntarily suppressible, though suppressing them usually comes with a feeling of discomfort, at least transiently [10,15]. Similarly, obsessive-compulsive disorder (OCD) is not among the psychiatric co-morbidities with FXTAS, although it falls within the spectrum of disorders under the FXAND umbrella [16,17].

Moreover, it is infrequent for OCD to first present later in life. OCD typically begins in childhood, frequently associated with TS, though OCD onset after the age of 30 has been reported in 11.3% of those adults with a lifetime diagnosis of OCD. [18,19]. OCDlike symptoms have also been reported in Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, and frontotemporal dementia, where cognitive decline and executive dysfunction may lead to obsessive thoughts and associated compulsive actions [20,21]. In this report, we describe a patient in the early stages of FXTAS, presenting very mild motor symptoms and white matter disease, who experienced an acute/subacute onset of executive dysfunction, obsessive-compulsive symptoms, and motor and vocal tics following a COVID-19 infection. The notable aspects of our case include the rapid onset of symptoms, the presence of tics and compulsive behaviors, and the potential role of COVID-19 infection in triggering these phenomena. The patient provided informed consent for both neuropsychological/motor and molecular testing, as approved by the institutional IRB of the University of California Davis Health Center. He also consented to the publication of his case history. All relevant information was gathered through a review of clinic visit notes and previous reports.

The patient was a 67-year-old Caucasian male with a premutation allele of the FMR1 gene with 84 CGG repeats, as measured by PCR and Southern blot analysis [22,23] and an FMR1 mRNA level 2.2- fold higher that in the general population, as measured by qRTPCR as previously described [24]. His family history was notable for a brother who was also a premutation carrier, as well as two daughters and nieces with premutation carrier status. There was a significant family history of sudden cardiac death on his paternal side and of cancer on both sides of the family, but no known family history of tics or OCD. He denied any prior psychiatric (including neurocognitive) disorders, describing himself only as a “slow test taker” in school. Despite this, he completed medical school, then residency and fellowship in radiology, establishing a successful career in medicine. His medical history included high-frequency hearing loss in his left ear and reduced vibratory sensation in his left great toe, both detected at 25 years of age. At age 55, he was diagnosed with hemochromatosis and deep vein thrombosis, for which he had been treated with coumadin and aspirin.

At age 60, he developed bilateral uveitis and was treated with methylprednisolone. He denied other autoimmune disorders. At age 60 he also developed a subclinical tremor that was slightly more severe in his left upper extremity. Brain MRI at that time revealed high intensity T2 signals in the middle cerebellar peduncles (left greater than right) as well as mild white matter disease. Although he was immunized against COVID-19, at age of 66, the patient contracted a prolonged and severe COVID-19 infection, with fever, malaise, prolonged fatigue, and cough. He was not hospitalized, and he was ill for approximately 6 weeks, but upon recovery, his wife, a pediatrician, reported observing the sudden onset of involuntary movements in his left upper extremity that were ticlike. These movements subsided within a few weeks, but he soon began to experience motor restlessness plus persistent cognitive difficulties including trouble with concentration and challenges in task prioritization. Additionally, episodes were reported where he struggled with organizing and communicating his thoughts.

He also exhibited difficulties with time management and a tendency toward obsessive thinking, characterized by excessive attention to details and a need for tasks to be performed in a specific ritualistic way. He reported that professional tasks like reviewing MRI images, which previously took him half an hour, now required several hours to complete. About three months later, the patient reported the reoccurrence of motor tics, primarily affecting his neck, trunk, and his left upper extremity, and vocal tics, characterized by spontaneous vocalizations and occasional changes in vocal tone. He described being able to suppress these involuntary movements and vocalizations but doing so caused unpleasant sensations and a persistent urge to perform the tics. Both the cognitive difficulties and the tic disorder had acute onset and remained stable over time, interfering with his work as a radiologist, leading to his retirement. At his most recent examination, his condition was stable. He was taking hydrochlorothiazide, folate, DHA, vitamin D, magnesium, curcumin, CoQ10, and lutein. He reported only mild positional tremors and denied balance problems, although he experienced occasional falls while hiking.

He also reported a persistent feeling of numbness, tingling and reduced sensitivity in his feet. Upon examination, his cranial nerves were intact, except he demonstrated significant bilateral hearing loss, which appeared to have increased since the last assessment, with an estimated 70% reduction. Muscle strength was normal throughout. Deep tendon reflexes were asymmetrical, with 1+ on the right and 2+ on the left biceps, 1+ at the knees, and absent at the ankles. The vibration sense was absent on the left foot and decreased on the right foot. There was an increased muscle tone in his left upper limb, while the right upper limb remained normal. Fingerto- nose testing revealed a subtle, subclinical intention tremor bilaterally. Primitive reflexes were absent, and his gait was normal. During tandem walking, he was able to maintain balance, though the mis stepped after six steps. Neuropsychological tests, such as Montreal Cognitive Assessment (MoCA), subtests of the Wechsler Adult Intelligence Scale (WAIS) IV, and the Behavioral Dyscontrol Scale (BDS-2), revealed a primary deficit in psychomotor speed accompanied by secondary weaknesses in aspects of executive functioning and information processing efficiency (Table 1).

Although the patient’s performance metrics did not indicate clinical impairment, the discrepancy from his previously wellabove- average functioning reflected a marked decline in cognitive efficiency, processing speed, and executive functioning, consistent with his reported subjective complaints. The Structured Clinical Interview for DSM (SCID) met no clinical criteria, although increased tangential speech patterns were noted. Given the presence of OCDlike behaviors and tics, treatment with an SSRI, such as sertraline or fluoxetine, was recommended (Table 1). Comparison of the most recent brain MRI with the MRI from 7 years previously revealed further increased hyperintensity in the left middle cerebellar peduncle (MCP sign) and enhanced diffuse deep white matter changes, particularly in the pons. Additionally, new high-signal intensity was noted in the splenium of the corpus callosum, which was absent in the earlier scan. There was also evidence of mild cortical atrophy with associated ventricular dilation (Figure 1).